PROJECT SUMMARY/ABSTRACT: OVERALL This is the third competing renewal application of the Vanderbilt-Ingram Cancer Center (VICC) SPORE in Breast Cancer. Using the well-established framework of a very active and strong multidisciplinary VICC Breast Cancer Program that is robustly supported by the SPORE mechanism, we have made significant progress in our current project period. Our highly successful Developmental Research Projects (DRP) and Career Enhancement Programs (CEP) continue to catalyze new ideas and new investigators in translational breast cancer research, including two projects in this continuing renewal. We are uniquely poised to complete the proposed work and to be even more productive in the years to come, thanks to an exceptional multidisciplinary program and established productive collaborations with other Breast Cancer Programs and SPOREs, as well as national and international collaborations. Our overall goal remains the same: To conduct collaborative, multidisciplinary and mechanism-based translational research that will have the highest possible impact for women and men with or at risk for breast cancer. After significant planning and internal and external advisory board evaluation, we propose four bi-directional translational projects addressing basic, translational and clinical research questions of importance in human breast cancer; Projects 1 and 2 are continuation projects, Projects 3 and 4 are new projects that have evolved from two CEP awards in the current funding cycle: Project 1 - Mechanisms of Resistance to Endocrine Therapy in ER+ Breast Cancer; Project 2 - Strategies to Improve Outcomes for TNBC Patients Integrating Subtype-specific Genomic and Immune-based Discoveries; Project 3 - Targeting the DNA Damage Response in Breast Cancer; Project 4 - Targeting Antigen Presentation to Improve Immunotherapy Responses in Breast Cancer. The application also includes DRP and CEP, and four highly integrated shared core resources: Administration and Engagement, Biostatistics and Bioinformatics, Pathology and Tissue Informatics, and Immunophenotyping. The cores bring innovative technology and resources, including additional personnel with project-specific expertise, to the overall VICC Breast SPORE Program and do not duplicate pre- existing shared resources available at VICC or Vanderbilt University Medical Center (VUMC). With a focus on human endpoints, six interventional therapeutic clinical trials are associated with the highly translational projects in this proposal, all based on extensive collaboration between world-class basic and clinical investigators. We have firmly established a true multidisciplinary team that successfully implements innovative clinical trials to test hypotheses that result from in vitro and patient studies, and that will continue to have productive translational collaborations with other Breast Cancer Programs and SPOREs as well as national and international groups.